Advancing the visibility of outer retinal integrity in neovascular age-related macular degeneration with high-resolution OCT.

OBJECTIVE: To compare the visibility and accessibility of the outer retina in neovascular age-related macular degeneration (nAMD) between 2 OCT devices. METHODS: In this prospective, cross-sectional exploratory study, differences in thickness and loss of individual outer retinal layers in eyes with nAMD and in age-matched healthy eyes between a next-level High-Res OCT device and the conventional SPECTRALIS OCT (both Heidelberg Engineering GmbH, Heidelberg, Germany) were analyzed. Eyes with nAMD and at least 250 nL of retinal fluid, quantified by an approved deep-learning algorithm (Fluid Monitor, RetInSight, Vienna, Austria), fulfilled the inclusion criteria. The outer retinal layers were segmented using automated layer segmentation and were corrected manually. Layer loss and thickness were compared between both devices using a linear mixed-effects model and a paired t test. RESULTS: Nineteen eyes of 17 patients with active nAMD and 17 healthy eyes were included. For nAMD eyes, the thickness of the retinal pigment epithelium (RPE) differed significantly between the devices (25.42 µm [95% CI, 14.24-36.61] and 27.31 µm [95% CI, 16.12-38.50] for high-resolution OCT and conventional OCT, respectively; p = 0.033). Furthermore, a significant difference was found in the mean relative external limiting membrane loss (p = 0.021). However, the thickness of photoreceptors, RPE integrity loss, and photoreceptor integrity loss did not differ significantly between devices in the central 3 mm. In healthy eyes, a significant difference in both RPE and photoreceptor thickness between devices was shown (p < 0.001). CONCLUSION: Central RPE thickness was significantly thinner on high-resolution OCT compared with conventional OCT images explained by superior optical separation of the RPE and Bruch's membrane.

Dynamics and patterns of recurrence in neovascular AMD during real-world management using automated fluid monitoring.

In this retrospective longitudinal observational study, data from one site of the Fight Retinal Blindness! Registry (University of Zurich, Switzerland) was used to investigate the quantity and distribution of recurrent fluid in neovascular age-related macular degeneration (nAMD). Study eye eligibility required treatment-naïve nAMD, receiving at least three anti-vascular endothelial growth factor injections, followed by a treatment discontinuation of at least six months and subsequence fluid recurrence. To quantify fluid, a regulatory approved deep learning algorithm (Vienna Fluid Monitor, RetInSight, Vienna, Austria) was used. Fifty-six eyes of 56 patients with a mean age of 76.29 ± 6.58 years at baseline fulfilled the inclusion criteria. From baseline to the end of the first treatment-free interval, SRF volume had decreased significantly (58.0 nl (IQR 10-257 nl) to 8.73 nl (IQR 1-100 nl), p < 0.01). The quantitative increase in IRF volume from baseline to the end of the first treatment-free interval was not statistically significant (1.35 nl (IQR 0-107 nl) to 5.18 nl (IQR 0-24 nl), p = 0.13). PED also did not reach statistical significance (p = 0.71). At the end of the second treatment discontinuation there was quantitatively more IRF (17.3 nl) than SRF (3.74 nl). In conclusion, discontinuation of treatment with anti-VEGF therapy may change the fluid pattern in nAMD.

A Systematic Prospective Comparison of Fluid Volume Evaluation across OCT Devices Used in Clinical Practice.

Objective: Treatment decisions in neovascular age-related macular degeneration (nAMD) are mainly based on subjective evaluation of OCT. The purpose of this cross-sectional study was to provide a comparison of qualitative and quantitative differences between OCT devices in a systematic manner. Design: Prospective, cross-sectional study. Subjects: One hundred sixty OCT volumes, 40 eyes of 40 patients with nAMD. Methods: Patients from clinical practice were imaged with 4 different OCT devices during one visit: (1) Spectralis Heidelberg; (2) Cirrus; (3) Topcon Maestro2; and (4) Topcon Triton. Intraretinal fluid (IRF), subretinal fluid (SRF), and pigment epithelial detachment (PED) were manually annotated in all cubes by trained human experts to establish fluid measurements based on expert-reader annotations. Intraretinal fluid, SRF, and PED volume were quantified in nanoliters (nL). Bland-Altman plots were created to analyze the agreement of measurements in the central 1 and 6 mm. The Friedman test was performed to test for significant differences in the central 1, 3, and 6 mm. Main Outcome Measures: Intraretinal fluid, SRF, and PED volume. Results: In the central 6 mm, there was a trend toward higher IRF and PED volumes in Spectralis images compared with the other devices and no differences in SRF volume. In the central 1 mm, the standard deviation of the differences ranged from ± 3 nL to ± 6 nL for IRF, from ± 3 nL to ± 4 nL for SRF, and from ± 7 nL to ± 10 nL for PED in all pairwise comparisons. Manually annotated IRF and SRF volumes showed no significant differences in the central 1 mm. Conclusions: Fluid volume quantification achieved excellent reliability in all 3 retinal compartments on images obtained from 4 OCT devices, particularly for clinically relevant IRF and SRF values. Although fluid volume quantification is reliable in all 4 OCT devices, switching OCT devices might lead to deviating fluid volume measurements with higher agreement in the central 1 mm compared with the central 6 mm, with highest agreement for SRF volume in the central 1 mm. Understanding device-dependent differences is essential for expanding the interpretation and implementation of pixel-wise fluid volume measurements in clinical practice and in clinical trials. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Inter and intradevice assessment of microperimetry testing in aging eyes.

Microperimetry (MP) is a psychometric examination combining retinal imaging and functional sensitivity testing with an increasing importance due to its potential use as clinical study outcome. We investigated the repeatability of pointwise retinal sensitivity (PWS) on the most advanced commercially available MP devices under their standard setting in a healthy aging population. Two successive MP examinations on both MP-3 (NIDEK CO., Ltd., Gamagori, Japan) and MAIA (CenterVue S.p.A. (iCare), Padova, Italy) were performed on healthy aging subjects in a randomized order. PWS repeatability was analysed for different macular regions and age groups using Bland-Altmann coefficients of repeatability (CoR). A total of 3600 stimuli from 20 healthy individuals with a mean age of 70 (11) years were included. Mean CoR in dB were ±4.61 for MAIA and ±4.55 for MP-3 examinations. A lower repeatability (p=0.005) was detected in the central millimetre on MAIA examinations. Higher subject age was associated with a lower repeatability of PWS on both devices (both p=0.003). Intra-device correlation was good (MAIA: 0.79 [0.76-0.81]; MP-3: 0.72 [0.68-0.76]) whereas a moderate mean inter-device correlation (0.6 [0.55-0.65]) could be detected. In conclusion, older subjects and the foveal region are associated with a worse pointwise repeatability.

Automated deep learning-based AMD detection and staging in real-world OCT datasets (PINNACLE study report 5).

Real-world retinal optical coherence tomography (OCT) scans are available in abundance in primary and secondary eye care centres. They contain a wealth of information to be analyzed in retrospective studies. The associated electronic health records alone are often not enough to generate a high-quality dataset for clinical, statistical, and machine learning analysis. We have developed a deep learning-based age-related macular degeneration (AMD) stage classifier, to efficiently identify the first onset of early/intermediate (iAMD), atrophic (GA), and neovascular (nAMD) stage of AMD in retrospective data. We trained a two-stage convolutional neural network to classify macula-centered 3D volumes from Topcon OCT images into 4 classes: Normal, iAMD, GA and nAMD. In the first stage, a 2D ResNet50 is trained to identify the disease categories on the individual OCT B-scans while in the second stage, four smaller models (ResNets) use the concatenated B-scan-wise output from the first stage to classify the entire OCT volume. Classification uncertainty estimates are generated with Monte-Carlo dropout at inference time. The model was trained on a real-world OCT dataset, 3765 scans of 1849 eyes, and extensively evaluated, where it reached an average ROC-AUC of 0.94 in a real-world test set.

Long-term effect of fluid volumes during the maintenance phase in neovascular age-related macular degeneration: results from Fight Retinal Blindness!

OBJECTIVE: To investigate the effect of macular fluid volumes (subretinal fluid [SRF], intraretinal fluid [IRF], and pigment epithelium detachment [PED]) after initial treatment on functional and structural outcomes in neovascular age-related macular degeneration in a real-world cohort from Fight Retinal Blindness! METHODS: Treatment-naive neovascular age-related macular degeneration patients from Fight Retinal Blindness! (Zürich, Switzerland) were included. Macular fluid on optical coherence tomography was automatically quantified using an approved artificial intelligence algorithm. Follow-up of macular fluid, number of anti-vascular endothelial growth factor treatments, effect of fluid volumes after initial treatment (high, top 25%; low, bottom 75%) on best-corrected visual acuity, and development of macular atrophy and fibrosis was investigated over 48 months. RESULTS: A total of 209 eyes (mean age, 78.3 years) were included. Patients with high IRF volumes after initial treatment differed by -2.6 (p = 0.021) and -7.4 letters (p = 0.007) at months 12 and 48, respectively. Eyes with high IRF received significantly more treatments (+1.6 [p < 0.001] and +5.3 [p = 0.002] at months 12 and 48, respectively). Patients with high SRF or PED had comparable best-corrected visual acuity outcomes but received significantly more treatments for SRF (+2.4 [p < 0.001] and +11.4 [p < 0.001] at months 12 and 48, respectively) and PED (+1.2 [p = 0.001] and +7.8 [p < 0.001] at months 12 and 48, respectively). DISCUSSION: Patients with high macular fluid after initial treatment are at risk of losing vision that may not be compensable with higher treatment frequency for IRF. Higher treatment frequency for SRF and PED may result in comparable treatment outcomes. Quantification of macular fluid in all compartments is essential to detect eyes at risk of aggressive disease.

Approved AI-based fluid monitoring to identify morphological and functional treatment outcomes in neovascular age-related macular degeneration in real-world routine (FRB!).

AIM: To predict antivascular endothelial growth factor (VEGF) treatment requirements, visual acuity and morphological outcomes in neovascular age-related macular degeneration (nAMD) using fluid quantification by artificial intelligence (AI) in a real-world cohort. METHODS: Spectral-domain optical coherence tomography data of 158 treatment-naïve patients with nAMD from the Fight Retinal Blindness! registry in Zurich were processed at baseline, and after initial treatment using intravitreal anti-VEGF to predict subsequent 1-year and 4-year outcomes. Intraretinal and subretinal fluid and pigment epithelial detachment volumes were segmented using a deep learning algorithm (Vienna Fluid Monitor, RetInSight, Vienna, Austria). A predictive machine learning model for future treatment requirements and morphological outcomes was built using the computed set of quantitative features. RESULTS: Two hundred and two eyes from 158 patients were evaluated. 107 eyes had a lower median (≤7) and 95 eyes had an upper median (≥8) number of injections in the first year, with a mean accuracy of prediction of 0.77 (95% CI 0.71 to 0.83) area under the curve (AUC). Best-corrected visual acuity at baseline was the most relevant predictive factor determining final visual outcomes after 1 year. Over 4 years, half of the eyes had progressed to macular atrophy (MA) with the model being able to distinguish MA from non-MA eyes with a mean AUC of 0.70 (95% CI 0.61 to 0.79). Prediction for subretinal fibrosis reached an AUC of 0.74 (95% CI 0.63 to 0.81). CONCLUSIONS: The regulatory approved AI-based fluid monitoring allows clinicians to use automated algorithms in prospectively guided patient treatment in AMD. Furthermore, retinal fluid localisation and quantification can predict long-term morphological outcomes.

Pediatric-Inspired Regimens in the Treatment of Acute Lymphoblastic Leukemia in Adolescents and Young Adults: A Systematic Review.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) have significantly worse outcomes than their younger counterparts. Current treatment guidelines rely mostly on non-randomized retrospective studies. We performed a systematic review of studies published within the last 15 years comparing pediatric-inspired regimens (PIR) versus adult-type regimens or performing an age-stratified analysis of outcomes in the AYA population. Due to the heterogeneity of data, a meta-analysis was not possible. However, the gathered data show a trend toward improvement in outcomes and an acceptable toxicity profile in patients treated with PIRs compared to conventional adult-type regimens. There is still room for further improvement, as older patients within the AYA population tend to perform poorly with PIR or conventional adult-type chemotherapy. Further randomized studies are needed to develop an optimal treatment strategy for AYA with ALL.

Progression Dynamics of Early versus Later Stage Atrophic Lesions in Nonneovascular Age-Related Macular Degeneration Using Quantitative OCT Biomarker Segmentation.

PURPOSE: To investigate the progression of geographic atrophy secondary to nonneovascular age-related macular degeneration in early and later stage lesions using artificial intelligence-based precision tools. DESIGN: Retrospective analysis of an observational cohort study. SUBJECTS: Seventy-four eyes of 49 patients with ≥ 1 complete retinal pigment epithelial and outer retinal atrophy (cRORA) lesion secondary to age-related macular degeneration were included. Patients were divided between recently developed cRORA and lesions with advanced disease status. METHODS: Patients were prospectively imaged by spectral-domain OCT volume scans. The study period encompassed 18 months with scheduled visits every 6 months. Growth rates of recent cRORA-converted lesions were compared with lesions in an advanced disease status using mixed effect models. MAIN OUTCOME MEASURES: The progression of retinal pigment epithelial loss (RPEL) was considered the primary end point. Secondary end points consisted of external limiting membrane disruption and ellipsoid zone loss. These pathognomonic imaging biomarkers were quantified using validated deep-learning algorithms. Further, the ellipsoid zone/RPEL ratio was analyzed in both study cohorts. RESULTS: Mean (95% confidence interval [CI]) square root progression of recently converted lesions was 79.68 (95% CI, -77.14 to 236.49), 68.22 (95% CI, -101.21 to 237.65), and 84.825 (95% CI, -124.82 to 294.47) mm/half year for RPEL, external limiting membrane loss, and ellipsoid zone loss respectively. Mean square root progression of advanced lesions was 131.74 (95% CI, -22.57 to 286.05), 129.96 (95% CI, -36.67 to 296.59), and 116.84 (95% CI, -90.56 to 324.3) mm/half year for RPEL, external limiting membrane loss, and ellipsoid zone loss, respectively. RPEL (P = 0.038) and external limiting membrane disruption (P = 0.026) progression showed significant differences between the 2 study cohorts. Further recent converters had significantly (P < 0.001) higher ellipsoid zone/RPEL ratios at all time points compared with patients in an advanced disease status (1.71 95% CI, 1.12-2.28 vs. 1.14; 95% CI, 0.56-1.71). CONCLUSION: Early cRORA lesions have slower growth rates in comparison to atrophic lesions in advanced disease stages. Differences in growth dynamics may play a crucial role in understanding the pathophysiology of nonneovascular age-related macular degeneration and for the interpretation of clinical trials in geographic atrophy. Individual disease monitoring using artificial intelligence-based quantification paves the way toward optimized geographic atrophy management. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Interventions to improve neurocognitive late-effects in pediatric and adolescent CNS tumor patients and survivors - a systematic review.

Introduction: Survival of children and adolescents diagnosed with central nervous system (CNS) tumors massively improved over the last decades due to better diagnostics, treatment, and supportive care. However, morbidity is still the highest of all cancer entities in this age group with neurocognitive late-effects being one of the most severe. Aim: With this systematic review, we aim to summarize interventions designed to prevent or improve neurocognitive late-effects in CNS tumor patients. Method: We searched PubMed on August 16th 2022 and included publications studying interventions for neurocognitive late-effects in pediatric and adolescent patients and survivors diagnosed with a CNS tumor. We included any form of neurocognitive intervention during treatment or following treatment completion. We considered all types of studies except for expert opinions and case reports. Results: The literature search resulted in 735 publications. We included 43 publications in the full text screening and 14 met our inclusion criteria. Of those, two assessed the impact of pharmacological interventions, three of exercise interventions, five of online cognitive training, and four assessed behavioral interventions. Different neuropsychological test batteries and imaging were used to measure the impact of the respective interventions. Most studies showed a positive impact of the interventions in single to several of the subtests used. Conclusion: We found several intervention studies indicating improvement of neurocognitive problems in children and adolescent CNS tumor survivors. In this population exercise interventions or online cognitive training might mitigate or improve neurocognitive late-effects.

Personalized treatment supported by automated quantitative fluid analysis in active neovascular age-related macular degeneration (nAMD)-a phase III, prospective, multicentre, randomized study: design and methods.

INTRODUCTION: In neovascular age-related macular degeneration (nAMD) the exact amount of fluid and its location on optical coherence tomography (OCT) have been defined as crucial biomarkers for disease activity and therapeutic decisions. Yet in the absence of quantitative evaluation tools, real-world care outcomes are disappointing. Artificial intelligence (AI) offers a practical option for clinicians to enhance point-of-care management by analysing OCT volumes in a short time. In this protocol we present the prospective implementation of an AI-algorithm providing automated real-time fluid quantifications in a clinical real-world setting. METHODS: This is a prospective, multicentre, randomized (1:1) and double masked phase III clinical trial. Two-hundred-ninety patients with active nAMD will be randomized between a study arm using AI-supported fluid quantifications and another arm using conventional qualitative assessments, i.e. state-of-the-art disease management. The primary outcome is defined as the mean number of injections over 1 year. Change in BCVA is defined as a secondary outcome. DISCUSSION: Automated measurement of fluid volumes in all retinal compartments such as intraretinal fluid (IRF), and subretinal fluid (SRF) will serve as an objective tool for clinical investigators on which to base retreatment decisions. Compared to qualitative fluid assessment, retreatment decisions will be plausible and less prone to error or large variability. The underlying hypothesis is that fluid should be treated, while residual persistent or stable amounts of fluid may not benefit from further therapy. Reducing injection numbers without diminishing the visual benefit will increase overall patient safety and relieve the burden for healthcare providers. TRIAL-REGISTRATION: EudraCT-Number: 2019-003133-42.

Optical coherence tomography-measured retinal nerve fiber layer thickness values compensated with a multivariate model and discrimination between stable and progressing glaucoma suspects.

PURPOSE: Our previously introduced multivariate model, compensating for intersubject variability, was applied to circumpapillary retinal nerve fiber layer (RNFL) values measured with optical coherence tomography in glaucoma suspects with or without prior progressive optic disc (OD) change in a series of confocal scanning laser tomography (CSLT, HRT III) measurements. METHODS: In this prospective study, OD change during CSLT follow-up was determined with strict, moderate, and liberal criteria of the topographic change analysis (TCA). Model compensation (MC) as well as age compensation (AC) was applied to RNFL sectors (RNFLMC vs. RNFLAC). Diagnostic performance of RNFLMC vs. RNFLAC was tested with an area under the receiver operating characteristic (AUROC) and was compared between methods. RESULTS: Forty-two glaucoma suspects were included. Patients without prior progressive OD change during the CSLT follow-up (= stable) had thicker RNFL thickness values in most areas and for all progression criteria. RNFLMC AUROC for the global RNFL (0.719) and the inferior quadrant (0.711) performed significantly better compared with RNFLAC AUROC (0.594 and 0.631) to discriminate between stable and progressive glaucoma suspects as defined by the moderate criteria of CSLT progression analysis (p = 0.028; p = 0.024). CONCLUSION: MC showed a slight but significant improvement in detection of subjects with prior progressive OD change among a group of glaucoma suspects, when compared to AC, which is the compensation method commonly used during OCT data evaluation in daily routine. Further studies are warranted to validate the present results.

Co-Occurrence of ANCA-Associated Vasculitis and Sjögren's Syndrome in a Patient With Acromegaly: A Case Report and Retrospective Single-Center Review of Acromegaly Patients.

Background: ANCA-associated vasculitis (AAV) and Sjögren's syndrome (SS) are uncommon autoimmune diseases. The co-occurrence in the same patient has been rarely described. Acromegaly has been associated with autoimmune thyroiditis, but the prevalence of other autoimmune disorders such as AAV and SS has not been evaluated in acromegaly. Methods: Characterization of a patient with acromegaly and two rare autoimmune diseases-SS and AAV (microscopic polyangiitis (MPA))-by autoantibody-array and whole exome sequencing (WES). Single-center retrospective review of medical records of acromegaly patients to explore the prevalence of diagnosed autoimmune diseases. Results: We report a Caucasian woman in her 50's with a serologically (anti-SSA/Ro, anti-MPO-ANCA antibodies) and histologically confirmed diagnosis of symptomatic SS and MPA. SS with MPO-ANCA positivity preceded MPA. An exploratory autoantigen array detected a broad spectrum of autoantibodies. WES revealed heterozygous carrier status of the PTPN22 mutation R620W, which is associated with an increased risk for autoimmunity. A similar combination of positive anti-SSA/Ro autoantibodies and ANCA was only present in 5/1184 (0.42%) other patients tested for both antibodies in our clinic over six years. Amongst 85 acromegaly patients seen at our clinic in a 20-year period, 12% had a clinically relevant associated immunological disease. Conclusion: We present a rare case of SS and AAV in a patient with acromegaly and multiple autoantibody specificities. Patients with SS and ANCA should be closely monitored for the development of (subclinical) AAV. Whether acromegaly represents a risk for autoimmunity should be further investigated in prospective acromegaly cohorts.

Syphilis Reactivates Latent Epstein-Barr Virus Reservoir via Toll-Like Receptor 2 and B-Cell Receptor Activation.

Latent Epstein-Barr virus (EBV) infection can clinically reactivate in immunosuppressed individuals causing lymphoproliferative disease and rarely hepatitis. In this study, we provide in vivo and in vitro evidence that Treponema pallidum infection can cause EBV reactivation with hepatitis in an immunocompetent patient. We report the diagnostic challenges and immunological findings of coinciding syphilis and EBV-associated hepatitis. Using an in vitro EBV-reactivation assay, we demonstrate that T pallidum reactivates latent EBV in a Toll-like receptor (TLR)2/B-cell receptor signaling-dependent manner. Epstein-Barr virus-associated reactivation or lymphoproliferation should be considered in infections with pathogens that activate TLR2.

Beneficial effects of lysosome-modulating and other pharmacological and nanocarrier agents on amyloid-beta-treated cells.

The progression of Alzheimer's disease (AD) is accompanied by disturbances of the endosome/lysosome (EL) system and there is accumulation of peptides of the AD-associated amyloid beta (Abeta) type in EL vesicles of affected neurons. EL modulating agents partially ameliorate the Abeta-mediated cell abnormalities. However, no extensive studies on the potential pharmaceutical applications of combinations of such agents and their synergistic effects have been performed. This study shows the beneficial anti-amyloid effects of several combinations of lysosomal modulators and other pharmacological and new nanobiotechnological agents. Some agents potentiated each other's action and some of them facilitated the anti-amyloid actions of memantine, a modifier of Ca2+-permeable channels involved in AD and one of the few drugs used for treatment of AD. Another compound used in nanobiotechnology ameliorated as a nanocarrier the beneficial effects of some of these potential pharmaceutical agents. They may be considered as additional drugs to improve the efficacy of the therapeutic approaches for AD and related neurodegenerative disorders.